Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle J N, Yoshimura A
Institute of Life Science, Kurume University, Aikawa-machi 2432-3 Kurume 839-0861, Japan.
EMBO J. 1999 Mar 1;18(5):1309-20. doi: 10.1093/emboj/18.5.1309.
The Janus family of protein tyrosine kinases (JAKs) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. However, compared with other kinases, little is known about cellular regulators of the JAKs. We have recently identified a JAK-binding protein (JAB) that inhibits JAK signaling in cells. In the studies presented here we demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2, whose phosphorylation is required for activation of kinase activity. Binding to the phosphorylated activation loop requires the JAB SH2 domain and an additional N-terminal 12 amino acids (extended SH2 subdomain) containing two residues (Ile68 and Leu75) that are conserved in JAB-related proteins. An additional N-terminal 12-amino-acid region (kinase inhibitory region) of JAB also contributes to high-affinity binding to the JAK2 tyrosine kinase domain and is required for inhibition of JAK2 signaling and kinase activity. Our studies define a novel type of regulation of tyrosine kinases and might provide a basis for the design of specific tyrosine kinase inhibitors.
蛋白质酪氨酸激酶（JAK）的Janus家族通过与细胞因子受体结合来调节参与细胞生长、分化和转化的细胞过程。然而，与其他激酶相比，人们对JAK的细胞调节因子知之甚少。我们最近鉴定出一种在细胞中抑制JAK信号传导的JAK结合蛋白（JAB）。在本文所展示的研究中，我们证明JAB特异性结合JAK2激活环中的酪氨酸残基（Y1007），其磷酸化是激酶活性激活所必需的。与磷酸化激活环的结合需要JAB的SH2结构域和一个额外的包含两个在JAB相关蛋白中保守的残基（Ile68和Leu75）的N端12个氨基酸（扩展SH2亚结构域）。JAB的另一个N端12氨基酸区域（激酶抑制区域）也有助于与JAK2酪氨酸激酶结构域的高亲和力结合，并且是抑制JAK2信号传导和激酶活性所必需的。我们的研究定义了一种新型的酪氨酸激酶调节方式，并可能为设计特异性酪氨酸激酶抑制剂提供基础。
